The invention relates to a compound having FSH receptor modulatory activity, to a pharmaceutical composition containing the same, as well as the use of said compound for FSH receptor mediated diseases.
Gonadotropins are important in a variety of bodily functions including metabolism, temperature regulation and the reproductive process. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. The hypophyseal gonadotropin FSH (follicle stimulating hormone) for example is released from the anterior pituitary under the influence of gonadotropin-releasing hormone and estrogens and plays a pivotal role in the stimulation of follicle development and maturation. FSH is the major hormone regulating secretion of follicular estrogens, whereas LH (luteinizing hormone) stimulates the production of follicular testosterone and induces ovulation (Sharp, R. M. Clin Endocrinol. 33:787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res. 35:301-342, 1979).
The actions of the FSH hormone are mediated by a specific plasma membrane receptor that is a member of the large family of G-protein coupled receptors. These receptors consist of a single polypeptide with seven transmembrane domains and are able to interact with the Gs protein, leading e.g. to the activation of adenylate cyclase.
The FSH receptor (FSHR) is a highly specific target in the ovarian follicle growth process and is exclusively expressed in the ovary. Blocking this receptor or inhibiting the signaling which is normally induced after FSH-mediated receptor activation will disturb follicle development and thus production of estrogens, ovulation and fertility. Low molecular weight FSH receptor antagonists, henceforth termed FSHR antagonists, could therefore form the basis for medical therapies that are in need of diminished production of estrogens and/or induction of anovulation.
Low molecular weight FSH receptor antagonists have been disclosed in International Applications WO 2008071455, WO 200807145 and WO 2008117175 and in van Straten, N. C. R. and Timmers, C. M. Annual Reports in Medicinal Chemistry 44:171-188, 2009 and van Straten, N. C. R. et al J. Med. Chem. 48:1697-1700, 2005.
Preventing or reversing endometriosis is an important goal in the field of women's health care. Endometriosis is a painful gynaecological condition that is characterized by the presence of endometrial tissue in sites outside of the uterine cavity. The prevalence rate is approximately 10% but this may be an underestimate because of the need to perform a laparoscopic procedure to determine the presence of disease. The disease affects women of reproductive age, the most common symptoms being painful menstruation (dysmenorrhoea), pain during intercourse (dyspareunia), painful bowel movement (dyschezia), chronic pelvic pain, heavy periods (menorrhagia), and infertility. If left untreated or inadequately treated endometriosis can either progress or spontaneously regress. In a significant number of women endometriosis is a chronic progressive disease manifesting itself as intractable pain, worsening quality of life, and infertility.
The etiology is unclear which also hampers an understanding of the symptomatic implications of the disease. Endometriosis produces an array of symptoms of varying severity with lack of correlation between stage of disease, disease load and degree of pain thereby causing confusion with clinical classification and delay in diagnosis. Known treatment options are drug therapy and conservative surgery.
Drug therapy is with analgesics, hormonal contraceptives which contain both estrogen and progestagen (Combined Oral Contraceptive (COC)) or progestagen only (Progestagen-Only Contraceptive (POC)), gonadotropin releasing hormone (GnRH) agonists, or other hormones e.g. danazol. Oral contraceptive regimens with combined use of an estrogen and a progestagen (COC) are widely used as first-line therapy in suspected or diagnosed endometriosis, owing to their property to provide cycle control, reduce menstrual flow and eradicate dysmenorrhoea, the most common symptom especially in early-stage disease. However, no single product offers sufficient efficacy in combination with a tolerable level of side effects. COCs may treat some of the symptoms well, but do not effectively suppress the progress of endometriosis and do not effectively treat chronic pelvic pain.
COCs produce initial decidualization of the endometrium by creating a state of pseudocyesis and later atrophy and thinning of the endometrium, thereby providing cycle control, reduction in menstrual flow and reduction of dysmenorrhoea. COCs may treat therefore menstruation-related symptoms but they do not completely suppress the growth of endometriotic lesions and associated chronic pelvic pain.
The mechanism of action of progestagens is initial decidualization of endometrium, followed by atrophy as a result of a direct suppressive effect on estrogen receptors in the endometrium. There is evidence that progestagens suppress matrix metalloproteinases at the molecular level thereby inhibiting the growth of ectopic endometrium. Medroxyprogesterone acetate is the most widely used progestagen for the treatment of endometriosis. Although available for oral administration, medroxyprogesterone acetate is usually administered as a depot formulation every 3 months. The side effects of POCs are multiple, the most common being breakthrough bleeding, nausea, fluid retention and breast tenderness.
GnRH agonists and GnRH antagonists down-regulate the Hypothalamus-Pituitary-Ovary axis by downregulation of the GnRH receptor and GnRH receptor-mediated signalling, resulting in a hypo-estrogenic menopausal state, endometrial atrophy, and amenorrhoea. Although very effective in reducing circulating levels of estrogens, multiple side effects related to menopausal symptoms as well as osteoporosis limit duration of treatment with GnRH agonists to 6 months.
Known drug treatments and/or conservative surgery offer temporary relief only and relapse rates can be as high as 50% with a major impact on fertility and quality of life. Moreover, a significant number of women aged 40-44 years require hysterectomy and bilateral salpingo-oophorectomy.
There is thus a strong need for early therapeutic intervention that improves on the above-mentioned shortcomings of available treatment options. The need is in particular for early therapeutic intervention that suppresses progression of disease and/or improves the side-effect profile (i.e. unscheduled bleeding, bone loss and menopausal symptoms) and improves fertility outcomes.